Cancer of the prostate is the most commonly diagnosed cancer in men and is the second most common cause of cancer death (Carter and Coffey, Prostate 16:39-48, 1990; Armbruster et al., Clinical Chemistry 39:181, 1993). If detected at an early stage, prostate cancer is potentially curable. However, a majority of cases are diagnosed at later stages when metastasis of the primary tumor has already occurred (Wang et al., Meth. Cancer Res. 19:179, 1982). Even early diagnosis is problematic because not all individuals who test positive in these screens develop cancer.
Present treatment for prostate cancer includes radical prostatectomy, radiation therapy, or hormonal therapy. With surgical intervention, complete eradication of the tumor is not always achieved and the observed re-occurrence of the cancer (12-68%) is dependent upon the initial clinical tumor stage (Zietman et al., Cancer 71:959, 1993). Thus, alternative methods of treatment including prophylaxis or prevention are desirable.
Prostate, testicular, and uterine cancers, are usually treated, in part, by the surgical removal of the affected organ. Up to 30% of the patients in the United States with potentially curable early-stage cancer, such as prostate cancer, will fail standard surgical or radiotherapy in 2004. In addition, patients with metastatic prostate cancer enjoy limited benefit of standard chemotherapy and hormone-based therapies. The metastases may not, however, be susceptible to surgical removal, or they may be too small to be readily detected. Enhancing the patient's immune response to the cancer, and particularly enhancing the response of cytotoxic T lymphocytes (“CTLs”) to the cancer, can aid in slowing or stopping the progress of the disease.
Immunotherapy may have great potential to improve these results, combining the tumor specificity of cell-mediated immunity with freedom from toxic chemotherapies.
Immunotherapy involves evoking an immune response against cancer cells based on their production of target antigens. Immunotherapy based on cell-mediated immune responses involves generating a cell-mediated response to cells that produce particular antigenic determinants, while immunotherapy based on humoral immune responses involves generating specific antibodies to cells that produce particular antigenic determinants.
Recent studies show that immunotherapy of cancer patients may be dramatically improved by the finding that CD8+CTLs recognize and kill tumor cells that display peptides from tumor-associated antigens within MHC Class I molecules. In clinical studies it has been found that effector CD8+ T cells play a major role in tumor regression. Several tumor antigens in prostate cancer models have been identified and HLA allele-specific peptides from those prostate cancer-associated antigens have been identified as CD8+ T cell epitopes. For example, HLA-A2.1 binding peptides were described that were derived from prostate specific antigen (PSA) (Correale et al., J Immunol 161:3186, 1998), prostate-specific membrane antigen (PSMA) (Tjoa et al., Prostate 28:65, 1996), prostate stem cell antigen (PSCA) (Kiessling et al., Int J Cancer 102:390, 2002), and prostate acid phosphatase (Peshwa et al., Prostate 36:129, 1998). For PSA, clinical trials are in progress using different vaccine strategies. However, there clearly is a need to identify additional antigens to aid in the diagnosis of a cancer of a reproductive organ, and for use as additional therapeutic agents.